SummaryOne of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27°C) and cold (18°C). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results.
Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is.
This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.

One of the central goals in evolutionary biology is to understand adaptation. Experimental evolution represents a highly promising approach to study adaptation. In this proposal, a freshly collected D. simulans population will be allowed to adapt to laboratory conditions under two different temperature regimes: hot (27°C) and cold (18°C). The trajectories of adaptation to these novel environments will be monitored on three levels: 1) genomic, 2) transcriptomic, 3) phenotypic. Allele frequency changes during the experiment will be measured by next generation sequencing of DNA pools (Pool-Seq) to identify targets of selection. RNA-Seq will be used to trace adaptation on the transcriptomic level during three developmental stages. Eight different phenotypes will be scored to measure the phenotypic consequences of adaptation. Combining the adaptive trajectories on these three levels will provide a picture of adaptation for a multicellular, outcrossing organism that is far more detailed than any previous results.
Furthermore, the proposal addresses the question of how adaptation on these three levels is reversible if the environment reverts to ancestral conditions. The third aspect of adaptation covered in the proposal is the question of repeatability of adaptation. Again, this question will be addressed on the three levels: genomic, transcriptomic and phenotypic. Using replicates with different degrees of genetic similarity, as well as closely related species, we will test how similar the adaptive response is.
This large-scale study will provide new insights into the importance of standing variation for the adaptation to novel environments. Hence, apart from providing significant evolutionary insights on the trajectories of adaptation, the results we will obtain will have important implications for conservation genetics and commercial breeding.

SummaryRecent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.

Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.

SummaryTargeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.

Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.

SummaryCancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.

Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.

SummaryChronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.

Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.

Max ERC Funding

2 499 875 €

Duration

Start date: 2018-06-01, End date: 2023-05-31

Project acronymDeFiNER

ProjectNucleotide Excision Repair: Decoding its Functional Role in Mammals

Researcher (PI)Georgios Garinis

Host Institution (HI)IDRYMA TECHNOLOGIAS KAI EREVNAS

Call DetailsConsolidator Grant (CoG), LS4, ERC-2014-CoG

SummaryGenome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.

Genome maintenance, chromatin remodelling and transcription are tightly linked biological processes that are currently poorly understood and vastly unexplored. Nucleotide excision repair (NER) is a major DNA repair pathway that mammalian cells employ to maintain their genome intact and faithfully transmit it into their progeny. Besides cancer and aging, however, defects in NER give rise to developmental disorders whose clinical heterogeneity and varying severity can only insufficiently be explained by the DNA repair defect. Recent work reveals that NER factors play a role, in addition to DNA repair, in transcription and the three-dimensional organization of our genome. Indeed, NER factors are now known to function in the regulation of gene expression, the transcriptional reprogramming of pluripotent stem cells and the fine-tuning of growth hormones during mammalian development. In this regard, the non-random organization of our genome, chromatin and the process of transcription itself are expected to play paramount roles in how NER factors coordinate, prioritize and execute their distinct tasks during development and disease progression. At present, however, no solid evidence exists as to how NER is functionally involved in such complex processes, what are the NER-associated protein complexes and underlying gene networks or how NER factors operate within the complex chromatin architecture. This is primarily due to our difficulties in dissecting the diverse functional contributions of NER proteins in an intact organism. Here, we propose to use a unique series of knock-in, transgenic and NER progeroid mice to decode the functional role of NER in mammals, thus paving the way for understanding how genome maintenance pathways are connected to developmental defects and disease mechanisms in vivo.

Max ERC Funding

1 995 000 €

Duration

Start date: 2016-01-01, End date: 2020-12-31

Project acronymDormantMicrobes

ProjectRevealing the function of dormant soil microorganisms and the cues for their awakening

Researcher (PI)Dagmar Woebken

Host Institution (HI)UNIVERSITAT WIEN

Call DetailsStarting Grant (StG), LS8, ERC-2014-STG

SummarySoils are considered the last scientific frontiers that harbor one of the most diverse microbial communities on Earth. It is hypothesized that this diversity allows for redundancy in microbial key processes, thereby ensuring ecosystem stability. Much of this functional redundancy is embodied in non-active, dormant microorganisms that represent the ‘microbial seed bank’, which is characterized by a high number of low abundant taxa. Based on the recent theory of a ‘dynamic rank-abundance curve’, it is hypothesized that the rare dormant organisms can be recruited to participate in a given function upon resuscitation with environmental cue(s). In this project I will test this hypothesis on a level that matters for ecosystem processes – the functional level – by an innovative approach combining stable isotope probing (SIP) and sequencing with process-level and single-cell activity analysis.
By testing 4 hypotheses, we will (1) reveal environmental cues that resuscitate dormant microorganisms involved in major soil functions and identify the activated microorganisms. The activity of the resuscitated communities will be analyzed at the process level, as well as at the single-cell by NanoSIMS, thereby allowing us to elucidate the impact of dormancy/resuscitation dynamics on targeted processes at the population and ecosystem level. (2) We will investigate the genetics of microbial dormancy-resuscitation strategies in a natural model environment for dormancy, an arid ecosystem, by metatranscriptome analysis of critical dormancy-resuscitation steps. (3) We will retrieve genomic information of primarily rare, but after resuscitation active, microorganisms involved in important soil processes, as they presumably contain so far unknown genomic potential. In summary, this project will generate essential knowledge on the stability of microbial key processes and on the diversity, the function and the genetics of the dormant majority in terrestrial ecosystems.

Soils are considered the last scientific frontiers that harbor one of the most diverse microbial communities on Earth. It is hypothesized that this diversity allows for redundancy in microbial key processes, thereby ensuring ecosystem stability. Much of this functional redundancy is embodied in non-active, dormant microorganisms that represent the ‘microbial seed bank’, which is characterized by a high number of low abundant taxa. Based on the recent theory of a ‘dynamic rank-abundance curve’, it is hypothesized that the rare dormant organisms can be recruited to participate in a given function upon resuscitation with environmental cue(s). In this project I will test this hypothesis on a level that matters for ecosystem processes – the functional level – by an innovative approach combining stable isotope probing (SIP) and sequencing with process-level and single-cell activity analysis.
By testing 4 hypotheses, we will (1) reveal environmental cues that resuscitate dormant microorganisms involved in major soil functions and identify the activated microorganisms. The activity of the resuscitated communities will be analyzed at the process level, as well as at the single-cell by NanoSIMS, thereby allowing us to elucidate the impact of dormancy/resuscitation dynamics on targeted processes at the population and ecosystem level. (2) We will investigate the genetics of microbial dormancy-resuscitation strategies in a natural model environment for dormancy, an arid ecosystem, by metatranscriptome analysis of critical dormancy-resuscitation steps. (3) We will retrieve genomic information of primarily rare, but after resuscitation active, microorganisms involved in important soil processes, as they presumably contain so far unknown genomic potential. In summary, this project will generate essential knowledge on the stability of microbial key processes and on the diversity, the function and the genetics of the dormant majority in terrestrial ecosystems.

Max ERC Funding

1 499 356 €

Duration

Start date: 2015-09-01, End date: 2020-08-31

Project acronymEPICLINES

ProjectElucidating the causes and consequences of the global pattern of epigenetic variation in Arabidopsis thaliana

SummaryEpigenetics continues to fascinate, especially the notion that it blurs the line between “nature and nurture” and could make Lamarckian adaptation via the inheritance of acquired characteristics possible. That this is in principle possible is clear: in the model plant Arabidopsis thaliana (Thale cress), experimentally induced DNA methylation variation can be inherited and affect important traits. The question is whether this is important in nature. Recent studies of A. thaliana have revealed a pattern of correlation between levels of methylation and climate variables that strongly suggests that methylation is important in adaptation. However, somewhat paradoxically, the experiments also showed that much of the variation for this epigenetic trait appears to have a genetic rather than an epigenetic basis. This suggest that epigenetics may indeed be important for adaptation, but as part of a genetic mechanism that is currently not understood. The goal of this project is to determine whether the global pattern of methylation has a genetic or an epigenetic basis, and to use this information to elucidate the ultimate basis for the global pattern of variation: natural selection.

Epigenetics continues to fascinate, especially the notion that it blurs the line between “nature and nurture” and could make Lamarckian adaptation via the inheritance of acquired characteristics possible. That this is in principle possible is clear: in the model plant Arabidopsis thaliana (Thale cress), experimentally induced DNA methylation variation can be inherited and affect important traits. The question is whether this is important in nature. Recent studies of A. thaliana have revealed a pattern of correlation between levels of methylation and climate variables that strongly suggests that methylation is important in adaptation. However, somewhat paradoxically, the experiments also showed that much of the variation for this epigenetic trait appears to have a genetic rather than an epigenetic basis. This suggest that epigenetics may indeed be important for adaptation, but as part of a genetic mechanism that is currently not understood. The goal of this project is to determine whether the global pattern of methylation has a genetic or an epigenetic basis, and to use this information to elucidate the ultimate basis for the global pattern of variation: natural selection.

Max ERC Funding

2 498 468 €

Duration

Start date: 2018-06-01, End date: 2023-05-31

Project acronymEPIDEMICSonCHIP

ProjectEPIDEMICS in ant societies ON a CHIP

Researcher (PI)Sylvia Maria Cremer-Sixt

Host Institution (HI)INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA

Call DetailsConsolidator Grant (CoG), LS8, ERC-2017-COG

SummaryLiving in societies amplifies the risk of getting sick, as pathogens can easily spread along the dense social interaction networks of the hosts. Sanitary care and the organisational structure of societies are expected to limit the risk of epidemics. Yet, how the defences of the individual group members scale-up, combine and synergise towards society-level protection, is poorly understood, as the majority of societies can only be studied via correlational and modeling approaches. Insect societies provide a powerful system for experimental studies, as whole societies are accessible for surveillance and manipulative approaches. We can monitor every behavioural interaction between all members, determine their effects on colony-wide disease spread and replicate experiments arbitrarily. The fitness effects of collective disease defences can be quantified, as they result in a single fitness measure of colony productivity. This is because all members of a social insect colony form a reproductive entity composed of the reproductive queens and males and their sterile workers. I will use an ant host–fungal pathogen system to find out how initial infection develops into an epidemic, and, in turn, how colony-level defence emerges from the interactions between its members. To infer effect from cause, I will not only observe the colony after initial infection of a subset of colony members, but also manipulate the sanitary behaviours and spatiotemporal interaction of host individuals. To this end, I will engineer an automatised platform, following the principles of lab-on-a-chip techniques, to individually target and manipulate colony members, and to quantify their behaviours. Fitness effects will be read out by the quantity and quality of reproductive offspring in the next generation. Such a long-term whole-colony approach is required for understanding the evolution of social immunity, that is, how disease shapes society and how society shapes disease.

Living in societies amplifies the risk of getting sick, as pathogens can easily spread along the dense social interaction networks of the hosts. Sanitary care and the organisational structure of societies are expected to limit the risk of epidemics. Yet, how the defences of the individual group members scale-up, combine and synergise towards society-level protection, is poorly understood, as the majority of societies can only be studied via correlational and modeling approaches. Insect societies provide a powerful system for experimental studies, as whole societies are accessible for surveillance and manipulative approaches. We can monitor every behavioural interaction between all members, determine their effects on colony-wide disease spread and replicate experiments arbitrarily. The fitness effects of collective disease defences can be quantified, as they result in a single fitness measure of colony productivity. This is because all members of a social insect colony form a reproductive entity composed of the reproductive queens and males and their sterile workers. I will use an ant host–fungal pathogen system to find out how initial infection develops into an epidemic, and, in turn, how colony-level defence emerges from the interactions between its members. To infer effect from cause, I will not only observe the colony after initial infection of a subset of colony members, but also manipulate the sanitary behaviours and spatiotemporal interaction of host individuals. To this end, I will engineer an automatised platform, following the principles of lab-on-a-chip techniques, to individually target and manipulate colony members, and to quantify their behaviours. Fitness effects will be read out by the quantity and quality of reproductive offspring in the next generation. Such a long-term whole-colony approach is required for understanding the evolution of social immunity, that is, how disease shapes society and how society shapes disease.

Max ERC Funding

1 991 564 €

Duration

Start date: 2018-04-01, End date: 2023-03-31

Project acronymEVOCHLAMY

ProjectThe Evolution of the Chlamydiae - an Experimental Approach

Researcher (PI)Matthias Horn

Host Institution (HI)UNIVERSITAT WIEN

Call DetailsStarting Grant (StG), LS8, ERC-2011-StG_20101109

SummaryChlamydiae are a unique group of obligate intracellular bacteria that comprises symbionts of protozoa as well as important pathogens of humans and a wide range of animals. The intracellular life style and the obligate association with a eukaryotic host was established early in chlamydial evolution and possibly also contributed to the origin of the primary phototrophic eukaryote. While much has been learned during the past decade with respect to chlamydial diversity, their evolutionary history, pathogenesis and mechanisms for host cell interaction, very little is known about genome dynamics, genome evolution, and adaptation in this important group of microorganisms. This project aims to fill this gap by three complementary work packages using experimental evolution approaches and state-of-the-art genome sequencing techniques.
Chlamydiae that naturally infect free-living amoebae, namely Protochlamydia amoebophila and Simkania negevensis, will be established as model systems for studying genome evolution of obligate intracellular bacteria (living in protozoa). Due to their larger, less reduced genomes compared to chlamydial pathogens, amoeba-associated Chlamydiae are ideally suited for these investigations. Experimental evolution approaches – among the prokaryotes so far almost exclusively used for studying free-living bacteria – will be applied to understand the genomic and molecular basis of the intracellular life style of Chlamydiae with respect to host adaptation, host interaction, and the character of the symbioses (mutualism versus parasitism). In addition, the role of amoebae for horizontal gene transfer among intracellular bacteria will be investigated experimentally. Taken together, this project will break new ground with respect to evolution experiments with intracellular bacteria, and it will provide unprecedented insights into the evolution and adaptive processes of intracellular bacteria in general, and the Chlamydiae in particular.

Chlamydiae are a unique group of obligate intracellular bacteria that comprises symbionts of protozoa as well as important pathogens of humans and a wide range of animals. The intracellular life style and the obligate association with a eukaryotic host was established early in chlamydial evolution and possibly also contributed to the origin of the primary phototrophic eukaryote. While much has been learned during the past decade with respect to chlamydial diversity, their evolutionary history, pathogenesis and mechanisms for host cell interaction, very little is known about genome dynamics, genome evolution, and adaptation in this important group of microorganisms. This project aims to fill this gap by three complementary work packages using experimental evolution approaches and state-of-the-art genome sequencing techniques.
Chlamydiae that naturally infect free-living amoebae, namely Protochlamydia amoebophila and Simkania negevensis, will be established as model systems for studying genome evolution of obligate intracellular bacteria (living in protozoa). Due to their larger, less reduced genomes compared to chlamydial pathogens, amoeba-associated Chlamydiae are ideally suited for these investigations. Experimental evolution approaches – among the prokaryotes so far almost exclusively used for studying free-living bacteria – will be applied to understand the genomic and molecular basis of the intracellular life style of Chlamydiae with respect to host adaptation, host interaction, and the character of the symbioses (mutualism versus parasitism). In addition, the role of amoebae for horizontal gene transfer among intracellular bacteria will be investigated experimentally. Taken together, this project will break new ground with respect to evolution experiments with intracellular bacteria, and it will provide unprecedented insights into the evolution and adaptive processes of intracellular bacteria in general, and the Chlamydiae in particular.